BRCA1 and BRCA2 gene mutation spectrum and a high frequency of BRCA1 185delAG among breast and ovarian cancer patients from Southern India.

Abstract Purpose In a developing country like India, genomic data sets for even the most clinically relevant genes like BRCA1 and BRCA2 is rather scarce. Also, there is a need to identify and screen population specific BRCA hotspots to pave a way for affordable genetic testing strategies in clinical practice. Method This is an ambispective study to evaluate an NGS based approach to identify pathogenic variants in BRCA1 and BRCA2 genes among 430 patients with Breast and Ovarian cancers. The target enrichment was carried out using the in-house designed Multiplex-PCR followed by targeted Next-generation sequencing (NGS) for BRCA1 and BRCA2. Also, allele-specific PCR based genotyping of del185AG was carried out in additional 120 patients. Results In this study, we have identified 100 BRCA1 and BRCA2 variants and based on ACMG 2015 guidelines, these variants were classified as 46 pathogenic, 9 likely pathogenic, and 45 VUS. Of these variants, three were novel, two with likely pathogenic, and one variant of uncertain significance (VUS). The 185delAG was identified as a recurrent mutation in the Southern Indian population accounting for 25.45% of the pathogenic variants. In addition, a family history of cancers of the breast, ovary, pancreas, or prostate (BOPP) was found to be associated with a higher risk of identifying a deleterious BRCA1/2 variant [OR 3.2 (95%CI 1.84–5.77) p ≤ 0.001]. Conclusions These results suggest that Multiplex PCR-NGS is a sensitive and specific strategy for BRCA testing. However, ASPCR-based genotyping of BRCA1(NM_007300.4): c.68_69del followed by targeted NGS would be a cost-effective approach in south Indian patients.